Identification of Novel Substrates for Aurka and LIMK2
Abstract
LIMK2 is a serine/threonine/tyrosine kinase that promotes tumor cell invasion and metastasis by phosphorylating cell proteins and altering their functions. There is a need to find tumor-specific substrates for LIMK2 in order to understand the downstream pathway of these substrates, their function, and how they are regulated by LIMK2. Recently, our labrotory identified LIMK2 as an excellent target for curing castration-resistant prostate cancer (CRPC). In this study, we identify two novel substrates for LIMK2 in CRPC: speckle-type POZ protein (SPOP), and Y-box binding protein-1 (YBX1). While LIMK2 negatively regulates SPOP, it positively regulates YBX1 − both by phosphorylation using in-vitro kinase assays. A study in our labrotory also proved that LIMK2 regulates Aurora A kinase (AURKA), where AURKA directly phosphorylates LIMK2. AURKA is a serine/threonine kinase that regulates cell cycle during mitosis; it is known to be upregulated, with uncontrolled activity, in many types of cancer, including prostate cancer. It is therefore important to identify new substrates for AURKA, especially in light of reported lethality in early embryonic mice, in association with AURKA-knockout. In other words, targeting AURKA directly may cause severe toxicity, a finding that has prevented direct inhibitors from passing Phase II clinical trials. In this study, we also identified SPOP and YBX1 as direct substrates for AURKA. Our results confirm what we know about the LIMK2/AURKA relationship: that AURKA negatively regulates SPOP and positively regulates YBX1. Targeting LIMK2 and AURKA indirectly through SPOP, YBX1 and its other substrates holds tremendous therapeutic potential in treating prostate cancer. With this, we open the door for researches to investigate the direct phosphorylation of SPOP and YBX1 in other types of cancer cells known to have overexpression in SPOP and/or YBX1.
Degree
Ph.D.
Advisors
Shah, Purdue University.
Subject Area
Cellular biology|Developmental biology|Endocrinology|Genetics|Oncology
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